Memory Hole (3 November): Forgetfulnesss

Scientific Misconduct Blog Memory Hole: Events of November 3rd

Quote of the day

FORGETFULNESS, n.
A gift of God bestowed in compensation for destitution of conscience.

48 years ago today: Thalidomide saga - the Voss question

On 3 November 1959 a written report was received by Chemie Grunenthal from neurologist Dr Ralf Voss of Dusseldorf reporting more adverse effects. Voss asked if Thalidomide could cause damage to the peripheral nervous system. Chemie Grunenthal replied that such effects had never been observed before. At the trial this proved to have been a lie.

8 years ago today: Hidden deaths, hidden science and uninformed consent in gene trials

On 3 November 1999 it was reported that deaths in clinical trials involving gene therapy were being hidden on demand from companies who were worried that it would "have an impact on their business". The Washington post reports:

"Scientists and drug companies have failed to notify the National Institutes of Health about six deaths that occurred in gene therapy experiments in the past 19 months".

"The researchers said they reported the deaths to the Food and Drug Administration, which keeps such information secret". "they are filing reports with demands for confidentiality or maintaining that they don't have to file them with the NIH at all".

Researcher Ronald Crystal "cited concerns about the impact on his business if the death were made public". "Schering-Plough also had demanded confidentiality for three recently filed reports of serious patient illness during gene therapy trials. The lead scientists in two of those studies determined that the complications "probably" were caused by the gene therapy; Schering-Plough officials had downgraded those assessments, saying they were "possibly related" to the therapy".

My oh my. Confidential science, confidential deaths, and information-free "informed" consent. No learning from the experience. Collusion by regulators. Is this science? Is it ethical? Did participants know that even their deaths would not contribute to knowledge? Would they have consented to take part had they known this?

Persons and companies named: Schering-Plough, Ronald Crystal of Cornell, Jeffrey Isner of Tufts, Carol Goodrich of Parke-Davis

But, two weeks later on 21 November 1999 the Washington post provided further details about one death - the totally unnecessary death of 18 year old Jesse Gelsinger at the University of Pennsylvania following a gene therapy experiment. It is reported that:

"it wasn't the first time the researchers had seen it. Unbeknown to Gelsinger, .... that monkeys the Penn team had similarly treated had succumbed in very much the same way". "The original [Gelsinger] consent form, reviewed by the NIH, clearly notified prospective participants that monkeys had died from a related treatment, but the final version given to patients eliminated any mention of the deaths." The NIH committee members say they also never got word of a significant change in the consent form. Neither the FDA nor the Penn team can explain today why the reference to monkey deaths was dropped.

"all four rhesus monkeys that had been given high doses of the first-generation virus had died in previous experiments".

Bit it wasn't only monkey data that had been hidden: Schering-Plough Corporation and the University of California had done preliminary trials in dying cancer patients, but "lowered the dose when two early participants experienced serious drops in blood pressure. But even at that lower dose – which was lower than the total dose eventually given to Gelsinger – two patients suffered serious stroke-like attacks". Wilson (the researcher) said he was only vaguely aware of those studies, none of which had been published in peer-reviewed journals until after Gelsinger's death. "But neither did Wilson reveal in his [own] written report at the meeting that one [earlier] patient had suffered an especially serious reaction to the treatment. Gelsinger was not informed of any of this.

Wilson, the researcher said: "If a mistake was made, we've got to own up to it and learn from it. Ultimately, the tragedy of Jesse's death would be if we don't learn anything." So let's think a little here - what have we learned over 8 years Dr Wilson?

Sources

• NIH Not Told Of Deaths in Gene Studies: Researchers, Companies Kept Agency in the Dark. The Washington Post, Nov 3, 1999
• Hasty Decisions in Race to a Cure?, the Washington Post, Nov 21, 1999

3 years ago today: WHO is wagging WHO

On 3 November 2004 the World Health Organization was accused of hiding a report on food advertising "after pressure from the food industry". Yet more irrelevant paperwork perhaps, but is hiding things a proper part of the remit of the WHO.

A censor is a man who knows more than he thinks you ought to.
Granville Hicks (1901-1982)

Source: "WHO buried report to please food industry" The Guardian, Nov 3 2004

2 years ago today: USA is the sickest

On 3 November 2005 a report published in Health Affairs (Schoen C et al. Health Affairs 2005) showed that the USA lagged far behind other countries in several indicators of healthcare despite far greater expenditure. The US doesn't rank at all on mortality statistics either (nor for that matter does the UK). Other studies show that even the wealthiest in the US are worse off. Technology is not necessarily the same as good science.

2 years ago today: Ethics for sale

On 3 November 2005 Bloomberg News reported on commercial (for profit) IRBs (ethics committees) and their rubber stamping of ethical approval of clinical studies for industry. I will highlight just one quotation:

Angela Bowen, who runs Western IRB and founded this ethics company, the largest commercial IRB in the US, had overseen clinical trials "for which doctors were criminally charged and jailed for lying to the FDA and endangering the lives of trial participants." But no action was taken against Western IRB. Angela Bowen told Bloomberg reporters that she "didn't see human safety issues in those trials."

So, lies in clinical research are apparently not a safety issue according to the owner of an ethics board?? Neither is hiding of unwanted results that are derived from the risk undertaken by human research participants.

In 2000, Angela Bowen reported that her company was receiving 1400 protocols per year, and charged about $550 per protocol. Business is going "straight up" she said. In April 2007 private equity firm Boston Ventures bought a majority stake in Western IRB for an undisclosed amount.

How did we reach this point?

See also: Slate, Ethics for Sale, by Carl Elliott and Trudo Lemmens and Annals of Internal Medicine (2000) 132 (6) 513-6

2 years ago today: Guidant sued for misrepresenting cardiac device

On 3 November 2005 New York Attorney General Eliot Spitzer sued Guidant Corporation (now Boston Scientific) for alleged fraud in connection with its sales of implantable cardiac defibrillators. Guidant had admitted that it failed to disclose information about defects in the device to doctors and patients. The device is expensive ($25,000). Doctors and patients might have chosen not to implant them had they realized that the benefit and risk were different from those conveyed.

The product was a faulty product, not because it sometimes failed, but because the combination package of product+science was not based on truthful conveying of that science. A later review concluded that (NYT 21/3/2006) Guidant had indeed been guilty of such misrepresentation.

In January 2006 "Guidant agreed to be acquired by Boston Scientific for $27 billion. Executives of Boston Scientific said they were considering changing the name of Guidant's heart device as part of a plan to rebuild physician confidence in its products (NYT)". Hmmmmm.

Perhaps confidence results from honest and transparent science - not linguistic manipulation. Did anyone go to prison here - after all patients likely died?

1 years ago today: Reward for bad science a £1 million bonus (TGN1412)

On 3 November 2006 Lawyers on behalf of six men who almost died in a medical trials criticised the US research company for awarding its boss a bonus of £920,000. The boss is Parexel chief executive Josef von Rickenbach. The trial was the TGN1412 study.

This disaster was caused in part by non-application of brainpower by the UK drug regulator (the MHRA). The MHRA then exonerated themselves (of something). See also the Hoofnagle trial discussed in the 23 October and 29 October memory holes. Learning = zero.

Source: BBC, Parexel chief gets a million £ bonus, 3 Nov 2006

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Memory Hole (2 November): The undoing of a thalidomide hero

19 years ago today: The undoing of William McBride, Thalidomide hero

On 2 November 1988 William McBride was found guilty of research misconduct and resigned from his research post in Australia. Twenty fine years earlier Mcbride had been the hero of thalidomide. He published a landmark letter in The Lancet on December 16th 1961 pointing out a curious coincidence he had noticed. He is credited with identifying the dangers of the drug.

His later research was problematical. The 1988 report stated: "we are forced to conclude that Dr. McBride did publish statements which he either knew were untrue or which he did no genuinely believe to be true, and in that respect was guilty of scientific fraud".

There are several illustrative aspects of this case:

1. McBride was also de-registered as a medical doctor. The de-registration was reversed in 1998 on the perverse basis that "his deregistration occurred as a result of work he did as a researcher, and not because of work he did as a medical practitioner". There were many reasons to restore McBride, but this was not an appropriate reason. What this says is that damaging patients through deliberately faulty research is acceptable because medical research and science are not part of being a doctor.
2. His exposure as a fraud was only as a result of the tireless work of the journalist Dr Norman Swan who broadcast about the fraud in December 1987. Sadly (and despite platitudes to the contrary), the mechanisms of science, journals, peer review and institutional procedures have demonstrated their inability to restrain fraudsters with any degree of reliability or honesty. In the case of McBride, institutional investigation was only launched after massive media exposure. The Australian Journal of Biological Sciences had already declined to publish a letter sent by McBride's colleagues Vardy and French. When Vardy had confronted McBride, he was sacked. The public press is likely to remain an important safeguard.

For additional useful notes see Fraud and Australian academics and Scientific fraud and the power structure of science both by Professor Brian Martin.

This is a sad but illustrative case given the very real contributions of McBride.

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Memory Hole (2 November): What else happened

Scientific Misconduct Blog Memory Hole: Events of November 2nd

8 years ago today: Lipstick on the BSE gorilla

On 2 November 1999 it was revealed that the UK government knew for years that some expensive cosmetics used bovine cow spleen, thymus or placenta (known to carry the agent causing Mad Cow Disease) and might infect people with cuts, scratches or abrasions. Experiments using mice showed that it was possible to infect them through skin cuts. Government made a deliberate decision not to inform the public to avoid an "unjustified fuss" and failed to ask what new bovine offal products were in the pipeline.

It seems to me unlikely this would be a major source of risk, and in retrospect it was less of a problem than some imagined. But the difficulty remains - why does government imagine that it has a legitimate role in suppression of scientific information and public discourse in this sort of paternalistic manner? A regulatory system should be a conduit for transparency, not a filter.

It is a bit like driving drunk - most of the time you will be OK, but just occasionally there will be an almighty crash.

"Officials kept quiet over possible BSE risk from cosmetics" The Guardian Nov 2 1999

3 years ago today: FDA publishes David Graham's Vioxx report

On 2 November 2004 the FDA posted an abridged version of study conducted by Dr. David J. Graham, associate director for science in the FDA's office of drug safety.

The report, was dated September 30 2004.
(the same day Merck withdrew Vioxx from the market).

Dr Graham managed to maintain his integrity within the FDA despite tremendous odds.
He refused to collude with the hiding of data.

2 years ago today: "Lilly is hiding information about Zyprexa"

On 2 November 2005 an interview with Dr. Curt Furberg was published (in Swedish) by the Swedish Academy of Pharmaceutical Sciences (SAPS). Furberg is Professor of Public Health Sciences Wake Forest University Baptist Medical Center. In the interview he revealed that (translated):

"Lilly is hiding negative information about Zyprexa." Furberg had seen secret Eli Lilly documents about the antipsychotic Zyprexa (olanzapine) in his capacity as an expert witness. "The big problem is that the industry knows about adverse effects not reported to the FDA, not to doctors, not to patients".

Followup: The secret Lilly documents were eventually revealed to the public in 2007.

Source: "Lilly is Hiding Negative Information About Zyprexa" - SAPS (in Swedish)

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NMT Medical and a new UK research scandal

An important new scandal involving inappropriate research procedure, misconduct in procedure, and possible misconduct in data analysis has blown up in the UK this week.

1. The saga involves a medical device, and the conduct and conclusions of the Migraine Intervention with STARflex Technology (MIST) I trial. A brief summary is below (a detailed press report is here)
2. MIST I was the first large trial to test whether the use of a new device to close a patent foramen ovale would reduce the incidence of migraine headaches. As it turns out, the results of the trial may have implications for the company which extend far beyond the issue of headache.
3. The study was sponsored by NMT Medical (of Boston, MA) and had two co-principal investigators who are as different as chalk and cheese a) Dr Peter Wilmshurst, a cardiologist and b) a so-called headache specialist Dr Andrew Dowson.
4. Dowson: Although Dowson described himself as a neurologist, he is not. More importantly, Dowson has restrictions on his medical practice following previous research misconduct (interesting fiddling of research records here, GMC restrictions here). Dowson states that NMT was fully aware of the research misconduct "undertakings" when he was chosen to be co-principal investigator.
5. Wilmshurst: By contrast, Wilmshurst is a highly respected cardiologist, and has worked in the field of PFO closure for 20 years. Wilmshurst was on the international planning committee that designed the MIST trial, and was originally selected to head up the trial before Dowson was put forward by the company as coinvestigator. NMT's website has multiple press releases naming Wilmshurst and Dowson as co-principal investigators. The protocol as submitted to the MREC (Multicentre IRB) in the UK states that "the study principal investigator will be shared by two physicians due to the nature of the trial".
6. According to Wilmshurst, his troubles with the sponsor began after he and Dowson presented the MIST I trial results at the ACC 2006 meeting. To the disappointment of many, MIST I was negative: PFO closure was no better at curing migraine than a sham procedure among people with PFOs and migraine with aura. One hypothesis explaining failure was that there may have been a high rate of residual shunts among patients. "Although a higher rate of residual shunts would help explain the negative outcome in MIST, it has much larger implications for a device already marketed in Europe for the treatment of cryptogenic stroke".
7. According to Wilmshurst (who has the emails to prove it) NMT officials instructed MIST investigators to send all patient echocardiograms to Wilmshurst for independent review immediately following the ACC. According to Wilmshurst, he ultimately reviewed the contrast echoes for all but one of the patients who underwent the scan at follow-up. At the TCT 2007 meeting last week, Dowson reported that the closure success rate was 94%, according to the implanting physician--in other words, a residual shunt rate of just 6% for the trial. Wilmshurst's review of the echocardiograms, however, suggested that the residual shunt rate was far higher--approximately one-third of the echocardiograms--a number he says was rejected by NMT. A second review of the echocardiograms (by Dr Luke Missault in Belgium) apparently yielded similar findings. NMT then ceased all communication with Wilmshurst and apparently refused further review of the echocardiograms stating that "to have echocardiograms reviewed at a single center would be a violation of study protocol, since it was not something that was specified in the patient consent process". !!!
8. Wilmshurst states that NMT has repeatedly "blocked his attempts to view the complete MIST I data set, has lied about whether echocardiograms from the MIST patients have been independently reviewed, and has massaged the data to portray its PFO device in the best possible light". Dr Andrew Dowson presented the "findings" at the TCT 2007 meeting (TCT 2007: Transcatheter Cardiovascular Therapeutics October 20 - 25, 2007, Washington, DC). It is not clear whether Dowson has the Echo data either, or whether and has the expertise to interpret it. "In fact, the first Wilmshurst learned that these data were going to be presented at TCT was when he arrived in Washington for the meeting and saw the trial listed in the TCT program."
9. Wilmshurst aired concerns about irregularities in the MIST trial and the activities of its sponsor, NMT Medical, during a presentation at this week's TCT 2007 meeting. NMT retaliated by claiming Wilshurst is not a principal investigator, cannot see the study data and has dropped Wilmshurst from the trial for so called "protocol violations" and so called "violations of the investigator's agreement". Asked for examples of these violations, the company declined to provide any "at this stage". NMT's lawyers also accused him of "breaching confidentiality agreements". Wilmshurst states that it is his duty to speak out "I cannot permit a confidentiality agreement to be used to allow NMT to make statements that are untrue in the belief that I or others who know that they are lying will remain silent". Wilmshurst also notes that he and other investigators at his center have "declined large consultancy payments from the sponsor".
10. Several other trial investigators are asking questions. One stated "There should be complete transparency of the MIST echo data with an independent core lab review of the studies that have already been done". The company provided a different excuse to this investigator implying that his proposal of transparency is somehow inappropriate because he "receives consultancy fees from [another] company, AGA". (? logic)
11. Wilmshurst and another colleagues (including Dr Simon Nightingale, who is also on the MIST steering committee) have repeatedly asked for the complete data collected in the MIST trial. According to Wilmshurst, the partial data they have seen, is "simply inconsistent". Wilmshurst also states that he and Nightingale have repeatedly asked for a full explanation as to why two patients, described as outliers, were excluded from secondary analyses of MIST I.
12. "For the past year, Wilmshurst says the company has responded to his emails only by threatening him with legal action and telling him that he is forbidden to speak publicly about the trial. Attempts were made by NMT to drop his center as a trial site (despite the fact that it had been the second-largest enroller). This was vetoed by the ethics board. Later however the center withdraw from after learning that the CRO running the trial (Matrix) had been ordered by the company not to provide clinical record forms to the center.
13. THE MREC (IRB) ordered NMT to meet with the steering committee and with the data safety and monitoring board. However, according to Wilmshurst, the company has more than once announced that it would hold this meeting, only to cancel at the last minute.
14. Dowson, the other investigator with headache expertise has now submitted the study publication to Circulation who have apparently accepted it. It is apparently going to be published "in a matter of weeks".
15. The company states that "outside independent auditors" have reviewed the data in the paper. "They seem to be comfortable at least with what's been presented to them . . . . Ethically it's important to get the data out there so we can do further studies."
16. So it seems OK for unknown "outside independent auditors" to (supposedly) see some data ("at least with what's been presented to them"), but not the clinical investigators or study authors.

The procedure in this trial may constitute research misconduct irrespective of any manipulation of the data. In fact it seems hard to know whether this is science or black magic. The corrupted (and unreformed) UK regulator the MHRA is now apparently also on the case, so perhaps yet another amusing obfuscation is heading our way. As assessors of black magic for the homeopathy industry, the MHRA are probably well placed to comment on this stuff. After a few years of silence and poor leadership the bleeding starts.

See NMT medical's code of ethics. There isn't much there about patients or research integrity, or the hiring of shonky investigators to bypass those who care.

The integrity of UK science isn't looking too good either. It's deja vu again and again for this type of problem.

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Memory Hole (1 November): The case of Philip Felig

Scientific Misconduct Blog Memory Hole: Events of November 1st

29 years ago today: Philip Felig - an important misconduct case begins

Around 1 November 1978 Helena Wachslicht-Rodbard submitted a publication to the The New England Journal of Medicine. The article concerned insulin receptors in patients with Anorexia. What followed became a case study in research misconduct, its definition and the typical reality of its handling.

The following is an abstracted summary of a compelling article on the affair from the New York Times of 1 Nov 1981 ("A fraud that shook the world of science").

NEJM sent the article out for peer review. Two reviewers recommend acceptance subject to revision, and one recommended rejection. Wachslicht-Rodbard began the process of revision. While revising the manuscript, Wachslicht-Rodbard received a rather similar paper from The American Journal of Medicine to review. That paper was written by Vijay Soman and his very famous superior, Philip Felig, of Yale. On reviewing the manuscript she found that it looked like her own. Some paragraphs were identical to those in her article and an equation she had devised to calculate receptor numbers was identical. Moreover it appeared that the authors of that paper had been the very reviewers who had recommend rejection of her own unpublished manuscript.

Felig admitted that he had received the manuscript for review, and had passed the paper onto his junior Soman. He did not regard this as inappropriate, and in terms of his rejection of the competing Wachslicht-Rodbard manuscript felt this was "touch and go who got priority" and that "the issue of conflict of interest needed consideration."

Wachslicht-Rodbard wrote to Relman at the NEJM accusing Soman and Felig of plagiarism.

Wachslicht-Rodbard became increasingly incandescent as it appeared that nothing of substance would be done and that the respective institutions were attempting a quiet cover-up. She noted that her own superior had tried to shut her up, and that she was ordered to stop using N.I.H. stationery and time to pursue her grievance. She stated that she was threatened with dismissal.

Soman admitted that he had kept the Wachslicht-Rodbard paper and had copied some of it, including the equation. Felig stated that "I severely reprimanded him for this".

Time went on. Wachslicht-Rodbard became increasingly angry and wrote to Dean Berliner of the Yale School of Medicine expressing doubts about the whole Soman-Felig paper, asking whether the study had been done at all. Felig himself however looked no further and simply stated that there was no problem. Berliner simply accepted this reassurance, and wrote to Wachslicht-Rodbard: "There is no question that the studies of Soman and Felig were done as described in their manuscript" and that he hoped she would consider the matter closed.

She refused. She stated that she would publicly denounce Soman and Felig at a scheduled scientific meeting. It was then agreed that the Soman+Felig paper would be "audited". In the meantime Wachslicht-Rodbard, totally disillusioned, resigned from the NIH, and left research.

Felig selected an "independent" auditor himself. Weeks passed, and nothing happened. However, Felig was then appointed Samuel Bard Professor and chairman of the Department of Medicine at Columbia, a key position. The Wachslicht-Rodbard charges were still confidential and those awarding the post had not been told anything. Felig felt the storm had passed, took Soman along to his new post, and recommended that Soman be appointed assistant professor.

The challenged Soman-Felig paper then appeared in the American Journal of Medicine that very month despite all questions remaining unanswered. Wachslicht-Rodbard was furious and suggested that a new "auditor" be found. New and strange problems were found with the paper (though the conclusions were identical to who own). For one thing, neither the psychotherapists nor the hospital where the studies had been done were named. A graph appeared to have been invented, with data falling neatly on a curve in an impossible manner.

An investigator (Flier) was appointed. Soman then claimed to have thrown away his raw data from the just-published manuscript. The investigator became suspicious. What raw data was available bore no relation to the paper. Soman then admitted to having invented most of the data. At least one of the six participants did not exist. Soman agreed to resign. The Soman-Felig paper would have to be retracted. All of his previous papers would have to be examined - but not to examine them would be far more scandalous.

Felig wrote apologetic letters. However, he did not inform his new prospective employers apart from vaguely mentioning the issue "in the course of discussing other things".

None of Soman's papers could be reconstructed from underlying data. Of 14 papers by Soman and others most appeared to have been fraudulent. Felig was a co-author, along with others, of most of these papers. Felig could no longer constrain the discussion and stories were circulating. Letters of retraction were sent to journals for 12 papers emanating from Yale Medical School, eight co-signed by Felig were retracted.

Felig met with his new employers but told them only of Soman's falsifications. He told nothing about the plagiarism, his rejection of the competing manuscript, or his failure to "discover in the course of a year what [the investigator] had been able to find out in three hours". He had not bothered to show any integrity. He simply moved to New York and started his new post. The rumors reached his new employers and everything Felig had not revealed was made available. A committee was established to review Felig's actions. It was concluded that Felig had failed to communicate incriminating information about himself.

"The Committee must conclude that the events disclosed by the correspondence, and Felig's attitude when asked about these events, reflect ethical insensitivity and the application of unacceptable standards to scientific research." The committee concluded "with the deepest regret" that Felig should not retain his professorship and posts at Columbia.

Felig was fired. But having not been himself guilty of fraud, he returned to Yale and even got some grants.

Helena Wachslicht-Rodbard decided never to return to research.

This all begs the question - what is scientific fraud? What of pretend naivete over the usual norms of scientific behavior? Felig in retrospect felt it was a "mistake" not to investigate his junior colleague's work. "I can't make sense of it. I consider the actions of the people at Columbia so outrageous that I have never been able to explain them in my own mind".

What of actions that are not fraud (as narrowly defined), but are otherwise grossly inappropriate and incompatible with the business of being a scientist? What of the whistleblower who was silenced and ignored? What of the deliberate failure to examine simple questions when it would seem mandatory to do so? What of the collusion with colleagues to "smooth" things over. If actions are not defined as fraud then they are clearly OK.

Source: Abstracted Summary of "A fraud that shook the world of science" - New York Times Nov 1 1981
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Psychopaths

I have been flying around the past few days, and attended (amongst other things) an excellent meeting on academic integrity. It will take a few days to catch up here. My flight today, I sat next to a man who insisted on sending a million text messages during takeoff despite repeated requests by airline staff not to do so. I have no idea whether this causes real risk to other passengers, but it made me wonder what sort of person would recklessly place his fellow travellers at increased risk of any amount. The same sort of person or company who might find it easy to behave like this or like this or like this or this and still sleep well and play with their kids I suppose.

"...the most devastating features of psychopathy are a callous disregard for the rights of others and a propensity for predatory and violent behaviors. Without remorse, psychopaths charm and exploit others for their own gain. They lack empathy and a sense of responsibility, and they manipulate, lie and con others with no regard for anyone's feelings."
Read on: here and here.

See also DSM IV criteria for psychopathy.

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Where's Osama?

A lighthearted joke mainly for pharmacologists and bone people before we get onto the meaty stuff.

Question: Where is Osama hiding?

Answer below the fold:


----------------------- (fold)


Fosamax (Alendronate)

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